The overall aim of this K-05 renewal is to support and expand the applicant's work in developing and improving pharmacotherapy for substance abuse as well as mentoring scientists embarking on such a career. The applicant has had a productive career in both areas, first at Yale and then Columbia University. The current K-05 was awarded in 2001 and enabled the applicant to leave his half-time position as Medical Director of CASA, a policy research center, and devote full time to his biomedical research and training activities at Columbia. Being at Columbia full- time made it possible for the applicant to expand his role in research, research oversight, and mentoring of faculty and trainees in the growing Division on Substance Abuse, which he directs. In these 4 years, aided by the effort of these talented faculty the Division continued to carry out the high quality of research it had begun and even expanded its scope. The applicant's current research focuses on developing and improving medications for treating cocaine, heroin, and marijuana dependence. Current funding for these areas is in hand for the first 3 years of this award since his Medication Development Center grant was recently renewed until September 2009. The Center includes 5 projects and two Cores, one of which funds innovative pilot projects. The Center Projects include: 1) human laboratory for studying opioids. Its current focus is on the rapidly rising problem of prescription opioids and will characterize the reinforcing efficacy of a number of different commonly abused opioid medications and the utility of buprenorphine to block/reduce these effects. 2) Imaging studies on cocaine which focus on relapse and the role of D-1 receptors and kappa opioid receptors. 3) A clinical trial with depressed cocaine abusers, the most common co-occurring disorder in cocaine. It examines not only the medication effect but also how to better identify which patients need such treatment and how to enhance it. 4) Agonist therapy for marijuana dependency. This is the first large placebo-controlled trial of an agonist agent for this common dependence, which is underestimated both in frequency and difficulty in stopping. 5) A human laboratory study on marijuana using a variety of agents, either to diminish withdrawal or to prevent relapse. In addition to the Center, the applicant will be developing projects relating to buprenorphine induction and withdrawal. Finally, he will continue active mentoring of young scientists and training at the medical student, resident, fellow, and young faculty levels.